WO1992019639A1 - Prodrogues glycosylees, leur procede de preparation et leurs utilisations - Google Patents

Prodrogues glycosylees, leur procede de preparation et leurs utilisations Download PDF

Info

Publication number
WO1992019639A1
WO1992019639A1 PCT/FR1992/000385 FR9200385W WO9219639A1 WO 1992019639 A1 WO1992019639 A1 WO 1992019639A1 FR 9200385 W FR9200385 W FR 9200385W WO 9219639 A1 WO9219639 A1 WO 9219639A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
acetyl
group
intermediate product
process according
Prior art date
Application number
PCT/FR1992/000385
Other languages
English (en)
French (fr)
Inventor
Jean-Claude Jacquesy
Jean-Pierre Gesson
Claude Monneret
Martine Mondon
Brigitte Renoux
Jean-Claude Florent
Michel Koch
François Tillequin
Hans Harald Sedlacek
Manfred Gerken
Cenek Kolar
Gilbert Gaudel
Klaus Bosslet
Jörg Czech
Dieter Hoffmann
Gerhard Seemann
Hans-Ulrich SCHOLRLEMMER
Gerhard Dickneite
Original Assignee
Laboratoires Hoechst
Behringwerke Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Hoechst, Behringwerke Ag filed Critical Laboratoires Hoechst
Priority to KR1019930703288A priority Critical patent/KR100254113B1/ko
Priority to JP4509828A priority patent/JP3053646B2/ja
Priority to US08/137,167 priority patent/US5561119A/en
Priority to AU17788/92A priority patent/AU673138B2/en
Priority to UA93003896A priority patent/UA56981C2/uk
Priority to CA002109304A priority patent/CA2109304C/en
Publication of WO1992019639A1 publication Critical patent/WO1992019639A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to glycosylated prodrugs, to a process for their preparation and to their use alone or with tumor-specific immunoenzymatic conjugates, in the treatment of cancers.
  • the present invention relates to prodrugs comprising modified anthracyclines which can be split in particular by the action of said tumor-specific immunoenzymatic conjugates, to give cytotoxic substances active towards tumor cells.
  • anti-tumor agents can be made specific vis-à-vis a tumor by adding a peptide which converts said agent into a pharmacologically inactive prodrug, but selectively activatable only at the tumor site by an enzyme present in quantities important at the tumor level (plasmin and plasminogen activator, in particular).
  • the peptide part of the prodrug has an amino acid sequence such that it will be enzymatically split from the antitumor agent part, by proteases such as plasmin or the plasminogen activator, so as to release the antitumor agent, under its active form in the tumor area.
  • the prodrugs activatable by hydrolytic enzymes may have a structure in which the peptide and the antitumor part are covalently linked via a self-immolable connector having a molecular structure such as the enzymatic peptide / self-immolable connector cleavage. will spontaneously cause the cleavage of its connection with the antitumor part.
  • the prodrugs described in this International Application can only be used in cancers which cause increased production of enzymes and more particularly proteases, at the tumor site;
  • these activating enzymes capable of cleaving the prodrugs described in this Application, are not found in sufficient quantity in human cancers, so that these prodrugs do not make it possible to obtain the desired selective toxicity (KD BAGSHAWE, Br J. Cancer, 1987, 56, 531).
  • International Application WO 88/07378, in the name of CANCER RESEARCH CAMPAIGN TECHNOLOGY LTD describes a therapeutic system which contains on the one hand an enzyme-antibody conjugate and on the other hand a prodrug which can be activated by the enzyme.
  • the antibody of the enzyme conjugate antibody recognizes a tumor-specific antigen and the enzyme is able to convert the prodrug into a cytotoxic agent.
  • This Application specifies that it is preferable to use enzymes other than mammalian enzymes, so as to prevent premature release of cytotoxic agent by endogenous enzymes.
  • modified nitrogen mustards such as p-bis-N- (2-chloroethyl) amino-benzylglutamic acid and its derivatives
  • modified nitrogen mustards such as p-bis-N- (2-chloroethyl) amino-benzylglutamic acid and its derivatives
  • prodrugs have the major drawback of retaining a non-negligible intrinsic cytotoxicity.
  • European Application 302 473 also describes a therapeutic system which contains two components and in which the enzyme-antibody conjugate located on the tumor tissue, splits a prodrug into a cytotoxic active compound. More specifically, the enzyme-antibody conjugates contain alkaline phosphatase (PA), penicillin V amidase (PVA) or cytosine deaminase (CD) and are used in combination with 4'-phosphate etoposide and its derivatives (or 7- (2-aminoethyl phosphate) mitomycin), with N- (p-hydroxyphenoxyacetyl) adriamycin or 5-fluorocytosine as prodrug.
  • PA alkaline phosphatase
  • PVA penicillin V amidase
  • CD cytosine deaminase
  • AKZO NV in the name of AKZO NV describes a method of site-specific in vivo activation of a prodrug in an animal, using an activator-specific substance conjugate with respect to target, the activator part of which allows the conversion of the prodrug into a pharmacologically active substance.
  • the activator is in particular an enzyme, such as lysozyme, of human origin, which is not present in the circulation or then in very small quantities and whose natural substrates are also absent from the circulation or from the surface of the cells non-targets.
  • the specific substance vis-à-vis the target is in particular an antibody directed against a tumor-specific antigen.
  • the prodrug can in particular comprise an anthracycline (doxorubicin, for example) modified by a chitin oligomer linked to the anthracyncline by an amino group at the level of carbonyl C 13 on the anthracycline or on the glycosylated part.
  • anthracycline doxorubicin, for example
  • a chitin oligomer linked to the anthracyncline by an amino group at the level of carbonyl C 13 on the anthracycline or on the glycosylated part doxorubicin, for example
  • the Applicant has therefore set itself the goal of providing prodrugs capable of being transformed into pharmacologically active substances in particular in the presence of an appropriate enzyme conjugate, which better meet the needs of the practice than the prodrugs of the prior art, in particular in that they are stable, in that they do not cause steric or electronic interference, during the enzymatic cleavage reaction and in that they provide the tumor site only, the active cytotoxic substance.
  • the present invention relates to anthracycline prodrugs, characterized in that they meet formula I below
  • R 1 , R 2 , R 3 which may be the same or different, represent a hydrogen atom or a hydroxyl group
  • R 4 represents a hydrogen atom, a hydroxyl group or a methoxy group
  • R represents a CO-CH 2 -R "group, in which R" esc a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxyl group, an alkoxyl group, an O-acyl group or an aryl group ;
  • R 5 and R 6 which may be the same or different, represent a hydrogen atom or a hydroxyl group;
  • R 7 represents a hydrogen atom or a hydroxyl group;
  • R 8 represents a group -CH 2 -OR or a group COOR 9 with
  • R 9 being a C 1 -C 3 alkyl or a hydrogen atom
  • R 10 and R 11 represent a hydrogen atom, a protective acyl group or an alkyl group
  • R 12 represents a hydroxyl group, an amino group, an amide group or a protective O-acyl group
  • benzyl -CH 2 is preferably in the para or ortho position of glycosyl oxygen
  • acyl and alkyl groups means groups comprising from 1 to 6 carbon atoms.
  • Y represents one or more electron-withdrawing groups
  • these are preferably in the ortho and / or para position of glycosyl oxygen and when Y represents one or more electron donor groups, these these are preferably in the meta position.
  • Y is in the para position and represents a hydrogen atom or an electron-withdrawing group and / or in the meta position and represents a hydrogen atom or an electron donor group,.
  • Y is in the ortho position and represents a hydrogen atom or an electron-withdrawing group and / or in the meta position and represents a hydrogen atom or an electron donor group.
  • the compounds of formula I in accordance with the invention include their various isomers.
  • anthracycline prodrugs according to the invention with 3 compartments, that is to say comprising an anthracycline, a self-immolating arm (para or ortho hydroxybenzylcarbamates) and an enzymatic substrate (ose) have the following advantages:
  • the intermediate arm is preferably, as specified above, a para or ortho hydroxybenzylcarbamate and the release of the active anthracycline from the 3-compartment prodrug is determined by two processes:
  • the preferred compounds of formula I especially comprise the following radicals:
  • R 1 , R 2 , R 3 are hydrogen atoms
  • R 4 is a methoxy group
  • R 5 and R 6 are hydroxyl groups
  • R is a group -CO-CH 3 or a group -CO-CH 2 OH
  • R 7 is a hydrogen atom, or a hydroxyl group
  • R 8 is a group -CH 2 -OAc, -CH 2 OH, -COOMe, or -COOH
  • R 10 and R 11 which may be the same or different represent a hydrogen atom or an Ac group
  • R 12 represents a group hydroxyl or an OAc group, which radicals R 8 , R 10 , R 11 and R 12 preferably have the following positions:
  • Y is a hydrogen atom, an NO 2 group or a chlorine atom, in para or ortho of glycosyl oxygen, and / or an OCH 3 group in meta of glycosyl oxygen.
  • the present invention also relates to a process for the preparation of a compound of formula I which can in particular be degraded by a glycosidase, characterized in that it comprises:
  • Z represents a hydroxyl group, an O-trialkylsilyl group or a group
  • R 8 , R 10 , R 11 and R 12 have the same meaning as above;
  • R ' represents a hydrogen atom or one of the following groups:
  • the benzyl -CH 2 is preferably in the para or ortho position of the phenol function, optionally modified (glycosylated or silylated);
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R have the same meaning as above,
  • Z is an O-trialkylesilyl group
  • it is advantageously desilylated with tetrabutyl ammonium fluoride, for example, prior to condensation with an ose.
  • the compound of formula A is a hydroxy benzyl glycosyl derivative of formula A 1 :
  • step (I) the p-hydroxybenzyl glycosyl derivative is obtained by:
  • the compound of formula A is a silylated derivative of formula An:
  • R ' has the same meaning as above and Z represents an O-dimethylthexylsilyl group or an O-tertiobutyldimethylsilyl group to provide, after coupling with an anthracycline of formula B, and condensation with a suitable ose, an anthracycline prodrug of formula I, as defined above,
  • the compound of formula A is an orthohydroxybenzyl glycosyl derivative of formula A 3 :
  • R 8 , R 10 , R 11 , R 12 and R ' have the same meaning as above,
  • Y is in the para position and represents an NO 2 group or a halogen atom and in the meta position and represents a hydrogen atom or a methoxy group;
  • benzyl CH 2 is in the ortho position relative to glycosyl oxygen
  • a subject of the present invention is also products comprising an anthracycline prodrug according to the invention and a tumor-specific enzyme-antibody conjugate, of formula II Ac-Sp-E, in which:
  • Ac is an antibody or a fragment thereof, which has specificity towards an antigen associated with a tumor, or is a biomolecule which tends to accumulate in a tumor, such as EGF (epidermal growth factor), ⁇ -TGF (transforming growth factor ⁇ ), PDGF (platelet-derived growth factor), IGF I + II (insulin growth factor I + II) or FGF a + b (fibroblastic growth factor a + b),
  • EGF epidermal growth factor
  • ⁇ -TGF transforming growth factor ⁇
  • PDGF platelet-derived growth factor
  • IGF I + II insulin growth factor I + II
  • FGF a + b fibroblastic growth factor a + b
  • E represents a glycosidase which is not immunogenic or has very low immunogenicity, preferably a mammalian glycosidase, such as a or ⁇ -glucosidase, ⁇ -galactosidase, a or ⁇ -mannosidase, ⁇ -fucosidase, N-acetyl- ⁇ -galactosaminidase, N-acetyl- ⁇ - and N-acetyl- ⁇ -glucosaminidase or ⁇ - glucuronidase,
  • Sp represents a group containing a sulfide or a disulfide of formula III or IV
  • R 14 being an oxygen atom or an NH group
  • n 1 or 2, for simultaneous, separate or spread over time use in cytostatic therapy.
  • both the anthracycline prodrug and the antibody conjugate can be associated with at least one pharmaceutically acceptable vehicle.
  • the coupling between the enzyme and the antibody, or a fragment thereof or a biomolecule is carried out using a method described in the literature (AH BLAIR and TI GHOSE, Immunology Methods, 1983, 59, 129-143; TI GHOSE et al., Methods in Enzymol., 1983, ⁇ , 280-333).
  • the glycolytic activity of the enzyme-specific, tumor-specific conjugates was determined, compared with p-nitrophenyl glycosides, at optimum pH.
  • the conjugate is administered to transplanted mice, then after having waited until the plasma enzyme level has returned to almost zero, l modified anthracycline (prodrug) is administered; it is observed if the growth of the tumor is stopped and if a regression takes place.
  • prodrugs 7, 14, 48b, 49b, 60 and 75b as well as the acetates 6, 13, 48a, 49a, 59 and 75a, which hydrolyze in vivo under the effect of enzymes and lead to one of the prodrugs mentioned above, are ⁇ -galactosides; prodrugs 22, 27c, 54c, 64c, 70c, 78b and 83c are ⁇ -glucuronides; prodrug 37 and its acetate 36 are ⁇ -glucosides.
  • These prodrugs are advantageously cleaved into daunorubicin or doxorubicin, as the case may be, in the presence of the appropriate conjugate, as defined above.
  • compositions according to the invention combining a prodrug with three compartments and a conjugate whose enzyme is an enzyme of non-circulating human origin make it possible to solve both the problem of immunological tolerance, of the specificity of action at the tumor site and as specified above, avoid steric or electronic interference during enzymatic cleavage.
  • the three-compartment prodrugs according to the invention can be cleaved by macrophages, granulocytes, thrombocytes or activated human tumor cells.
  • these activated cells release ⁇ -glucuronidase capable of effectively cleaving (hydrolysis) the glucuronyl compounds-self-immolable arm-drugs.
  • prodrugs are then directly usable as a medicament for the treatment of mala dies where macrophages, granulocytes, thrombocytes or activated human tumor cells are involved.
  • the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.
  • EXAMPLE 1 synthesis of the ⁇ -D-galactopyranoside of N- (4-hydroxy-benzyloxycarbonyl) daunorubicin (7).
  • the benzylic bromination of the compound (1) obtained is carried out either in the presence of N-bromosuccinimide (NBS) and photochemical activation and provides only compound 2, or in the presence of NBS and benzoyl peroxide and mainly provides compound 2 and small amounts of the aldehyde derivative 3.
  • NBS N-bromosuccinimide
  • the displacement of the bromine of derivative 2 is carried out in acetone or in ether-acetone with (or without) (Bu 3 Sn) 2 O and provides the derivative 4, while the reduction of the aldehyde derivative 3 by borohydride of sodium provides additional amounts of compound 4.
  • Activation of the OH group of derivative 4 is carried out using N-succinimidyl chloroformate or disuccinimidyl carbonate (DSC).
  • Method I 8.9 g of p. cresol, 8.9 g of penta-O-acetyl-D-galactopyranose and 0.56 g of ZnCl 2 are mixed and brought to 160oC and maintained at this temperature for 30 minutes, according to the HELFERICH method. After cooling to 60oC, the reaction medium is taken up in 400 ml of CH 2 CI 2 , washed twice with 400 ml of water, then with a solution of sodium hydroxide ( ⁇ 1N), until the aqueous phase is hardly colored.
  • Method II 11 g of penta-O-acetyl-D-galactopyranose, 11 g of p. cresol and 2.4 g of ZnCl 2 are dissolved in 8 ml of a mixture of acetic acid and acetic anhydride (95/5 v / v) and brought to 120oC. The reflux is maintained for 2 hours.
  • a solution of 1.89 g of compound 2 in 80 ml of acetone is mixed with an equal volume of an aqueous solution of 0.1 N silver nitrate.
  • the mixture is stirred at 25 ° C for 2 h then acetone is evaporated under reduced pressure and the remaining aqueous phase is extracted with CH 2 CI 2 , washed with water, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.
  • the dry residue obtained (1.52 g) is then purified on a "flash" silica column (solvent: ethyl hexaneacetate: 60/40 v / v).
  • Product 4 (0.94 g) is obtained with a yield of 56%.
  • Compound 4 is transformed into succinimido-carbonate by coupling with succinimido-chloroformate.
  • succinimido-chloroformate A solution of 2 g of N-hydroxysuccinimide in 11 ml of ethanol is mixed with a solution of 1 g of potassium hydroxide in 30 ml of ethanol. The product formed is filtered, washed with ether and dried overnight at 40oC under vacuum. 2.40 g of the potassium salt of hydroxysuccinimide are thus obtained (Yield: 94%).
  • reaction medium is taken up in ethyl acetate, then extracted with a saturated NaCl solution.
  • methyl 2-bromomethylphenyl- (2,3,4-tri-O-acetyl- ⁇ -D-glucopyranosyl) uronate 23 obtained from methyl 2-methyl-phenyl- (2,3,4 -tri-O-acetyl- ⁇ -D-glucopyranosyl) uronate, as described in GN BOLLENBACK et al. (J. Am. Chem. Soc, 1955, 22/3310), is converted into product 24 (and / or into product 25) then product 24 is transformed into product 26.
  • the carbonate 26 is prepared using commercially available 4-nitrophenyl chloroformate.
  • derivative 32 is prepared either by synthesis from derivative 28 (2-tertiobutyldimethylsilyloxy-benzaldehyde), which is reduced in the presence of NaBH 4 to give compound 29, activation by 4-nitrophenyl chloroformate leads to derivative 30 which is condensed with daunorubicin, product 32 is then obtained by deprotection with KF, or by enzymatic hydrolysis of product 14 (see example 2) with ⁇ -galactosidase.
  • the silylated derivative 31 (2 mg, 0.0025 mmol) is dissolved in THF (0.1 ml). 0.2 ml of an aqueous KF solution (0.1 g per ml) is then added. After 12 hours at room temperature a usual extraction provides 32.
  • Product 32 can advantageously be condensed with sugar to provide products 27a, 27b or 27c
  • Alcohol 29 (135 mg, 0.56 mmol) is dissolved in ethyl acetate (0.82 ml). Pyridine (0.081 ml) is then added and then 4-nitro phenyl chloroformate (275 mg, 2.4 eq.). After overnight at room temperature, the solvent is evaporated. Chromatography on silica gel provides carbonate 30 (206 mg, 91%).
  • 2,3,4,6-tetra-O-acetyl- ⁇ -D-bromoglucose (2 g, 4.8 mmol) is dissolved in 20 ml of chloroform.
  • An extraction is carried out with 50 ml of water.
  • the organic phase obtained is washed successively with a 1N NaOH solution (2 ⁇ 50 ml), with an HCl solution (1N), then with water, dried and concentrated to dryness.
  • the crude product obtained is then recrystallized from ethanol to give 33 (0.5 g, 23%).
  • Method B By activation by the DSC (cf.: preparation of 19, example 3) of compound 34 (yield 80%).
  • derivative 38 is prepared either by synthesis or by enzymatic hydrolysis, in accordance with Example 5 (derivative 32).
  • an enzyme suspension (20 ⁇ l, 5 U of ⁇ -D-glucosidase (20 mg of ⁇ -D-glucosidase in 400 ⁇ l of water plus 80 ⁇ l of ethanol) is added to 37oC for 15 min.
  • Compound 38 can advantageously be condensed with another sugar and in particular a derivative of glucuronic acid to provide the products 20, 21 or 22.
  • dibromo derivative 44 Hydrolysis of dibromo derivative 44 provides aldehyde 45 which can be reduced by NaBH 4 to derivative 46, while hydrolysis of derivative 43 leads to a mixture of 45 and 46.
  • 4-nitrophenyl formate is used for activating derivative 46 and coupling 47 with daunorubicin and doxorubicin leads to derivatives 48a and 49a respectively.
  • methyl peracetyl- ⁇ -D-glucopyranoside uronate bromide is condensed with 2-hydroxy-5-nitrobenzaldehyde in the presence of Ag 2 O at room temperature.
  • compound 58 could not be purified and isolated on a silica column.
  • carbonate 63 is obtained, which is not purified but immediately reacted with daunorubicin according to the conditions described to prepare 54.
  • the medium is filtered, diluted with CH 2 CI 2 (30 ml), washed with water (3 ⁇ 30 ml), dried over Na 2 SO 4 and evaporated to provide the 2 , 3,4-tri-O-acetyl- ⁇ -D-methyl-glucuronide of (4-hydroxymethyl-2-chloro) -phenyl (1.00 g; 64%).
  • the residue obtained provides, after chromatography on a column of silica gel 60H (dichloromethane-methanol, 95/5 v / v), 2,3,4-tri-O-acetyl- ⁇ -D-methylglucuronide from N- (4 -hydroxy-3-chloro-benzyloxycarbonyl) -doxorubicin (78a) (0.691 g; 41%).
  • the DNM-arm self-immolable compound (deglycosidated product) disappears with a half-life of 45 h, this is less than 16 h for the same product at pH 7.3 and daunomycin appears in the medium.
  • the product is stable in plasma.
  • FIG. 1 illustrates the results obtained with the derivative 48b.
  • This figure 1 represents the concentrations as a function of time of daunorubicin (1), of the derivative
  • the deglycoside derivative 60 is not detected, because of its high rate of disappearance.
  • Figure 3 shows the results obtained when the derivative 54c is incubated with recombinant human ⁇ -glucuronidase concentrated at 37oC and pH 7.2.
  • the concentration of 54c is 530 ⁇ g / ml.
  • FIG. 4 shows the results obtained in the presence of ⁇ -glucuronidase diluted to 1/100 (other conditions identical to those of FIG. 3).
  • the deglycoside derivative 54 has a half-life of around 5.3 h.
  • FIG. 5 shows the results obtained when the pro drug 70c is incubated with human ⁇ -glucuronidase (0.45 U / ml) at 37oC and at pH 7.2.
  • the controls consist of tumor cells exposed to a culture medium. Four wells are prepared for each anthracycline concentration and for the control. After 65 hours, 50 ⁇ l of MTT (2.5 mg / ml in PBS) are added.
  • MTT will be reduced in the presence of living cells by an insoluble red formazan dye. After 7 to 24 hours of additional incubation (depending on the cells used), the supernatant is removed. The formazan dye is dissolved by the addition of 100 ⁇ l of DMSO to each well, followed by gentle stirring.
  • the extinction is measured for each well, at 492 nm (Multiscan 340 CC Fa. Flow photometer).
  • the results are expressed as the extinction ratio after incubation with the products over the extinction obtained with the controls.
  • the coefficient of variation is less than 15%.
  • Prodrugs have significantly reduced cytotoxicity compared to doxorubicin.
  • the acetates 6, 13 and 48a are hydrolyzed in vivo respectively in 7, 14 and 48b.
  • the prodrugs in accordance with the invention are synthesized of the daunomycin-self-immolable arm- ⁇ -glucuronides, doxorubicin-self-immolable arm- ⁇ -glucuronides and doxorubicin-self-immolable arm- ⁇ -galactosides in accordance with the method described above. .
  • the substances are incubated at 37 ° C with recombinant ⁇ -glucuronidase (or coffee bean ⁇ -galactosidase) (1 U / ml), at a pH of 7.2 to 6.8, and determined in vitro the kinetics of disappearance of the glycoside as well as the kinetics of formation of daunomycin and doxorubicin using a reverse phase HPLC.
  • ⁇ -glucuronidase or coffee bean ⁇ -galactosidase
  • the arm-free ⁇ -glucuronide used as a comparison substance, is cleaved 50 to 100 times slower than the daunomycin-arm-glucuronide compounds or the doxorubicin-arm-glucuronide compounds.
  • the substituents present on the aromatic cycle of this self-immolable arm (hydroxybenzylcarbamates, for example) have a influence on the cut-off kinetics of the glycosyl derivative and on the decomposition kinetics of the anthracycline product + self-immolable arm.
  • B 1 is a ⁇ -glucuronide and B 4 is an NO 2 group or a chlorine atom.
  • Other substituents also make it possible to obtain the desired kinetics.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
PCT/FR1992/000385 1991-04-30 1992-04-29 Prodrogues glycosylees, leur procede de preparation et leurs utilisations WO1992019639A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
KR1019930703288A KR100254113B1 (ko) 1991-04-30 1992-04-29 글리코실화된 프로드러그로서의 화합물 및 그 제조방법과의 약품으로의 이용
JP4509828A JP3053646B2 (ja) 1991-04-30 1992-04-29 グリコシル化したプロドラック、その製法と用途
US08/137,167 US5561119A (en) 1991-04-30 1992-04-29 Glycosylated prodrugs, their method of preparation and their uses
AU17788/92A AU673138B2 (en) 1991-04-30 1992-04-29 Glycosylated anthracycline prodrugs
UA93003896A UA56981C2 (uk) 1991-04-30 1992-04-29 Антрациклінові проліки, спосіб їх одержання та композиція для використання у цитостатичній терапії
CA002109304A CA2109304C (en) 1991-04-30 1992-04-29 Glycosylated prodrugs, and their processes of preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9105326A FR2676058B1 (fr) 1991-04-30 1991-04-30 Prodrogues glycosylees, leur procede de preparation et leur utilisation dans le traitement des cancers.
FR91/05326 1991-04-30

Publications (1)

Publication Number Publication Date
WO1992019639A1 true WO1992019639A1 (fr) 1992-11-12

Family

ID=9412404

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1992/000385 WO1992019639A1 (fr) 1991-04-30 1992-04-29 Prodrogues glycosylees, leur procede de preparation et leurs utilisations

Country Status (16)

Country Link
US (1) US5561119A (uk)
EP (1) EP0511917B1 (uk)
JP (1) JP3053646B2 (uk)
KR (1) KR100254113B1 (uk)
AT (1) ATE144523T1 (uk)
AU (1) AU673138B2 (uk)
CA (1) CA2109304C (uk)
DE (1) DE69214712T2 (uk)
DK (1) DK0511917T3 (uk)
ES (1) ES2096735T3 (uk)
FR (1) FR2676058B1 (uk)
GR (1) GR3022344T3 (uk)
HK (1) HK1008020A1 (uk)
IE (1) IE921369A1 (uk)
UA (1) UA56981C2 (uk)
WO (1) WO1992019639A1 (uk)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0642799A1 (en) * 1993-09-09 1995-03-15 BEHRINGWERKE Aktiengesellschaft Improved prodrugs for enzyme mediated activation
EP0648503A1 (en) * 1993-09-22 1995-04-19 BEHRINGWERKE Aktiengesellschaft Pro-prodrugs, their production and use
EP0751144A1 (en) 1995-06-27 1997-01-02 Pharmachemie B.V. Novel anthracycline prodrugs, method for preparation as well as their use in selective chemotherapy
EP0795334A2 (de) * 1996-03-12 1997-09-17 Hoechst Aktiengesellschaft Neuartige Prodrugs für die Therapie von Tumoren und entzündlichen Erkrankungen
EP0595133A3 (de) * 1992-10-27 1998-11-04 BEHRINGWERKE Aktiengesellschaft Prodrugs, ihre Herstellung und Verwendung als Arzneimittel
US6610299B1 (en) * 1989-10-19 2003-08-26 Aventis Pharma Deutschland Gmbh Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates
WO2013138343A1 (en) 2012-03-16 2013-09-19 The Johns Hopkins University Controlled release formulations for the delivery of hif-1 inhibitors

Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475486B1 (en) * 1990-10-18 2002-11-05 Aventis Pharma Deutschland Gmbh Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates
FR2712888B1 (fr) * 1993-11-23 1996-02-09 Bioeurope Utilisation de alpha-D-alkylglucopyranosides et esters de ceux-ci pour la préparation de prodrogues capables de traverser la barrière hématoencéphalique, prodrogues obtenues et précurseurs de celles-ci.
DE4417865A1 (de) * 1994-05-20 1995-11-23 Behringwerke Ag Kombination von Tumornekrose-induzierenden Substanzen mit Substanzen, die durch Nekrosen aktiviert werden, zur selektiven Tumortherapie
US5525606A (en) 1994-08-01 1996-06-11 The United States Of America As Represented By The Department Of Health And Human Services Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines
DE19512484A1 (de) 1995-04-04 1996-10-17 Bayer Ag Kohlenhydratmodifizierte Cytostatika
DE19617851A1 (de) 1996-05-03 1997-11-13 Hoechst Ag Nukleinsäurekonstrukte mit Genen kodierend für Transportsignale
GB2318471A (en) * 1996-10-18 1998-04-22 Stc Submarine Systems Ltd Semiconductor laser amplifiers for transient suppression in optical wavelength division multiplex networks
DE19720312A1 (de) * 1997-05-15 1998-11-19 Hoechst Ag Zubereitung mit erhöhter in vivo Verträglichkeit
DE19751587A1 (de) 1997-11-21 1999-07-29 Hoechst Marion Roussel De Gmbh Onkogen- oder virusgesteuerte Expressionssysteme
AU1825299A (en) 1997-12-17 1999-07-05 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
US6180095B1 (en) 1997-12-17 2001-01-30 Enzon, Inc. Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
US6624142B2 (en) 1997-12-30 2003-09-23 Enzon, Inc. Trimethyl lock based tetrapartate prodrugs
US5965119A (en) * 1997-12-30 1999-10-12 Enzon, Inc. Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents
US6962702B2 (en) 1998-06-22 2005-11-08 Immunomedics Inc. Production and use of novel peptide-based agents for use with bi-specific antibodies
US6214330B1 (en) 1998-07-13 2001-04-10 Enzon, Inc. Coumarin and related aromatic-based polymeric prodrugs
US6043367A (en) * 1998-09-30 2000-03-28 Roffler; Steve Proactive antitumor compounds
US6413507B1 (en) * 1999-12-23 2002-07-02 Shearwater Corporation Hydrolytically degradable carbamate derivatives of poly (ethylene glycol)
US7220824B1 (en) 2000-08-28 2007-05-22 Bayer Aktiengesellschaft Integrin-mediated drug targeting
US6436386B1 (en) 2000-11-14 2002-08-20 Shearwater Corporation Hydroxyapatite-targeting poly (ethylene glycol) and related polymers
US7829074B2 (en) 2001-10-18 2010-11-09 Nektar Therapeutics Hydroxypatite-targeting poly(ethylene glycol) and related polymers
EP1219634A1 (en) * 2000-12-27 2002-07-03 Bayer Aktiengesellschaft Cytostatic-glycoconjugates having specifically cleavable peptidic linking units
DK1362053T3 (da) * 2001-02-20 2008-03-10 Enzon Inc Terminalt forgrenede polymere linkere og polymere konjugater indeholdende disse
EP1238678A1 (en) * 2001-03-08 2002-09-11 Bayer Aktiengesellschaft Enzyme-activated cytostatic conjugates with integrin ligands
US7629309B2 (en) 2002-05-29 2009-12-08 Zystor Therapeutics, Inc. Targeted therapeutic proteins
US7560424B2 (en) 2001-04-30 2009-07-14 Zystor Therapeutics, Inc. Targeted therapeutic proteins
WO2003073988A2 (en) 2002-02-28 2003-09-12 A & D Bioscience, Inc. Glycuronamides, glycosides and orthoester glycosides of fluoxetine, analogs and uses thereof
US20050107310A1 (en) * 2002-03-19 2005-05-19 Holick Michael F. Carboxylic acid glycuronides, glycosamides and glycosides of quinolones, penicillins, analogs, and uses thereof
US20050255038A1 (en) * 2002-04-12 2005-11-17 A And D Bioscience, Inc. Conjugates comprising cancer cell specific ligands, a sugar and diagnostic agents and uses thereof
EP1549323A2 (en) * 2002-05-07 2005-07-06 A & D Bioscience, Inc. Conjugates comprising central nervous system active drug
US20050215487A1 (en) * 2002-06-27 2005-09-29 Holick Michael F Conjugates comprising an nsaid and a sugar and uses thereof
SI2269656T1 (sl) 2002-07-15 2014-11-28 Board Of Regents, The University Of Texas System Izbrana protitelesa, ki se veĹľejo na aminofosfolipide, in njihova uporaba v zdravljanju raka
US20040152769A1 (en) * 2002-11-09 2004-08-05 Ekwuribe Nnochiri Nkem Modified carbamate-containing prodrugs and methods of synthesizing same
DE10256982A1 (de) * 2002-12-05 2004-06-24 Schering Ag Neue Effektor-Konjugate, Verfahren zu Ihrer Herstellung und Ihre Pharmazeutische Verwendung
CA2534639C (en) 2003-07-31 2013-07-30 Immunomedics, Inc. Anti-cd19 antibodies
US7902338B2 (en) 2003-07-31 2011-03-08 Immunomedics, Inc. Anti-CD19 antibodies
AU2005282562A1 (en) * 2004-09-08 2006-03-16 Government Of The United States Of America Represented By The Secretary, Department Of Health And Human Services Beta-glucuronidase cleavable prodrugs of O6-alkylguanine-DNA alkyltransferase inactivators
US7825096B2 (en) * 2004-09-08 2010-11-02 The United States Of America As Represented By The Department Of Health And Human Services O6-alkylguanine-DNA alkyltransferase inactivators and beta-glucuronidase cleavable prodrugs
SI3248613T1 (sl) 2005-07-18 2022-04-29 Seagen Inc. Konjugati beta-glukuronidni linker-zdravilo
US20070185135A1 (en) * 2005-12-30 2007-08-09 Pharmaessentia Corp. Drug-Polymer Conjugates
US20100323976A1 (en) * 2007-06-14 2010-12-23 Johannes Maria Franciscus Gerardus Aerts Novel anti-inflammatory pro-drugs
JP5404624B2 (ja) * 2007-08-01 2014-02-05 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ 選択的な抗腫瘍薬として有用なピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン−グリコシドプロドラッグ
AU2008317383B2 (en) 2007-10-23 2013-11-14 Nektar Therapeutics Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom
EP2614837A1 (en) 2007-11-09 2013-07-17 Affitech Research AS Anti-VEGF antibody compositions and methods
EP2098533A1 (en) * 2008-03-07 2009-09-09 Pharmachemie B.V. Esters of glucuronide prodrugs of anthracyclines and method of preparation and use in tumor-selective chemotherapy
BR122017015900A2 (pt) 2008-05-07 2019-09-10 Biomarin Pharm Inc ácido nucleico e células
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy
EP3075386B1 (en) 2009-06-17 2019-10-16 BioMarin Pharmaceutical Inc. Formulations for lysosomal enzymes
FR2960153B1 (fr) 2010-05-20 2012-08-17 Centre Nat Rech Scient Nouveaux bras autoreactifs et prodrogues les comprenant
US9023813B2 (en) * 2011-04-13 2015-05-05 NuTek Pharma Ltd. Synthesis and use of glycoside derivatives of propofol
CN109843919A (zh) 2016-03-25 2019-06-04 西雅图基因公司 用于制备聚乙二醇化的药物-接头及其中间体的方法
GB201617466D0 (en) 2016-10-14 2016-11-30 Medimmune Ltd Pyrrolobenzodiazepine conjugates
GB201702031D0 (en) 2017-02-08 2017-03-22 Medlmmune Ltd Pyrrolobenzodiazepine-antibody conjugates
LT3544636T (lt) 2017-02-08 2021-06-25 Adc Therapeutics Sa Pirolobenzodiazepino-antikūno konjugatai
CN110430901A (zh) 2017-03-24 2019-11-08 西雅图基因公司 制备葡糖苷酸药物-接头及其中间体的方法
HUE059828T2 (hu) 2017-04-18 2023-01-28 Medimmune Ltd Pirrolobenzodiazepin konjugátumok
AU2018316532B2 (en) 2017-08-18 2022-11-24 Medimmune Limited Pyrrolobenzodiazepine conjugates
GB201803342D0 (en) 2018-03-01 2018-04-18 Medimmune Ltd Methods
GB201806022D0 (en) 2018-04-12 2018-05-30 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
US20210386864A1 (en) 2018-11-05 2021-12-16 Bayer Pharma Aktiengesellschaft Cytostatic conjugates with integrin ligands
KR102258299B1 (ko) * 2019-03-21 2021-05-28 고려대학교 산학협력단 대장암 선택적 항암 치료진단제
WO2021057840A1 (en) * 2019-09-25 2021-04-01 Peking University Senolytic and antiinflammatory prodrugs and methods of use thereof
WO2021056270A1 (en) * 2019-09-25 2021-04-01 Peking University Senolytic prodrugs and methods of use thereof
US20220362387A1 (en) * 2019-09-25 2022-11-17 Peking University Senolytic and antiinflammatory prodrugs and methods of use thereof
WO2023057812A1 (en) 2021-10-04 2023-04-13 Vincerx Pharma Gmbh Compounds, pharmaceutical compositions, and methods for the treatment, prevention, or management of hyperproliferative disorder
WO2023057813A1 (en) 2021-10-04 2023-04-13 Vincerx Pharma Gmbh Compounds, pharmaceutical compositions, and methods for the treatment, prevention, or management of hyperproliferative disorders
WO2023057814A1 (en) 2021-10-04 2023-04-13 Vincerx Pharma Gmbh Compounds, pharmaceutical compositions, and methods for the treatment, prevention, or management of hyperproliferative disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0410366A2 (de) * 1989-07-26 1991-01-30 BEHRINGWERKE Aktiengesellschaft Anthracyclin-Derivate

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035566A (en) * 1975-09-25 1977-07-12 Sidney Farber Cancer Institute, Inc. N-trifluoroacetyladriamycin-14-alkanoates and therapeutic compositions containing same
WO1981001145A1 (en) * 1979-10-18 1981-04-30 Univ Illinois Hydrolytic enzyme-activatible pro-drugs
GB8705477D0 (en) * 1987-03-09 1987-04-15 Carlton Med Prod Drug delivery systems
US4975278A (en) * 1988-02-26 1990-12-04 Bristol-Myers Company Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells
US4952394A (en) * 1987-11-23 1990-08-28 Bristol-Myers Company Drug-monoclonal antibody conjugates
DK0454783T3 (da) * 1989-01-23 1995-10-16 Akzo Nobel Nv Sted-specifik in vivo aktivering af terapeutiske lægemidler
JPH075572B2 (ja) * 1989-08-18 1995-01-25 積水化学工業株式会社 ２―［２―（２―ヒドロキシフェニル）ビニルピラジンおよびその製造法
DE3935016A1 (de) * 1989-10-20 1991-04-25 Behringwerke Ag Glycosyl-etoposid-prodrugs, verfahren zu ihrer herstellung und ihre anwendung in kombination mit funktionalisiertem tumorspezifischen enzym-konjugaten

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0410366A2 (de) * 1989-07-26 1991-01-30 BEHRINGWERKE Aktiengesellschaft Anthracyclin-Derivate

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610299B1 (en) * 1989-10-19 2003-08-26 Aventis Pharma Deutschland Gmbh Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates
US5955100A (en) * 1992-10-27 1999-09-21 Behringwerke Aktiengesellschaft Prodrugs their preparation and use as pharmaceuticals
US6146658A (en) * 1992-10-27 2000-11-14 Hoechst Aktiengesellschaft Prodrugs, their preparation and use as pharmaceuticals
EP0595133A3 (de) * 1992-10-27 1998-11-04 BEHRINGWERKE Aktiengesellschaft Prodrugs, ihre Herstellung und Verwendung als Arzneimittel
EP0647450A1 (en) * 1993-09-09 1995-04-12 BEHRINGWERKE Aktiengesellschaft Improved prodrugs for enzyme mediated activation
EP0642799A1 (en) * 1993-09-09 1995-03-15 BEHRINGWERKE Aktiengesellschaft Improved prodrugs for enzyme mediated activation
EP0648503A1 (en) * 1993-09-22 1995-04-19 BEHRINGWERKE Aktiengesellschaft Pro-prodrugs, their production and use
AU681180B2 (en) * 1993-09-22 1997-08-21 Behringwerke Aktiengesellschaft Pro-prodrugs, their production and use
US5877158A (en) * 1993-09-22 1999-03-02 Behringwerke Aktiengesellschaft Pro-prodrugs, their production and use
US5710135A (en) * 1995-06-27 1998-01-20 Pharmachemie B.V. Anthracycline prodrugs, method for preparation as well as their use in selective chemotherapy
EP0751144A1 (en) 1995-06-27 1997-01-02 Pharmachemie B.V. Novel anthracycline prodrugs, method for preparation as well as their use in selective chemotherapy
US5935995A (en) * 1996-03-12 1999-08-10 Heochst Aktiengesellschaft Prodrugs for the therapy of tumors and inflammatory disorders
EP0795334A2 (de) * 1996-03-12 1997-09-17 Hoechst Aktiengesellschaft Neuartige Prodrugs für die Therapie von Tumoren und entzündlichen Erkrankungen
EP0795334B1 (de) * 1996-03-12 2006-02-01 Sanofi-Aventis Deutschland GmbH Neuartige Prodrugs für die Therapie von Tumoren und entzündlichen Erkrankungen
WO2013138343A1 (en) 2012-03-16 2013-09-19 The Johns Hopkins University Controlled release formulations for the delivery of hif-1 inhibitors

Also Published As

Publication number Publication date
FR2676058A1 (fr) 1992-11-06
IE921369A1 (en) 1992-11-04
JP3053646B2 (ja) 2000-06-19
KR100254113B1 (ko) 2000-04-15
ES2096735T3 (es) 1997-03-16
GR3022344T3 (en) 1997-04-30
ATE144523T1 (de) 1996-11-15
UA56981C2 (uk) 2003-06-16
AU1778892A (en) 1992-12-21
DE69214712T2 (de) 1997-05-07
EP0511917B1 (fr) 1996-10-23
JPH06506687A (ja) 1994-07-28
FR2676058B1 (fr) 1994-02-25
HK1008020A1 (en) 1999-04-30
DK0511917T3 (da) 1997-04-01
AU673138B2 (en) 1996-10-31
CA2109304C (en) 2002-01-15
US5561119A (en) 1996-10-01
EP0511917A1 (fr) 1992-11-04
DE69214712D1 (de) 1996-11-28
CA2109304A1 (en) 1992-10-31

Similar Documents

Publication Publication Date Title
EP0511917B1 (fr) Prodrogues glycosylées, leur procédé de préparation et leurs utilisations
KR930006757B1 (ko) 종양세포에 세포독성물질의 전달시 전구약물과 배합되는 항체-효소 결합체
EP0751144B1 (en) Novel anthracycline prodrugs, method for preparation as well as their use in selective chemotherapy
JPH09202796A (ja) 新規なパクリタキセルプロドラッグ、製造方法およびその選択的化学療法における使用
EP2571528A1 (fr) Nouveaux bras autoréactifs et prodrogues les comprenant
EP0069678A2 (fr) Dérivés de 3-fucosyl-N-acétyl lactosamine, leur préparation et leurs applications biologiques
JPH03502934A (ja) 腫瘍抑制サツカライド包合体
JPS6328434B2 (uk)
TWI807423B (zh) 抗體藥物複合體
JPH0616690A (ja) アントラサイクリン類のグリコシルプロドラツグ
JP3293086B2 (ja) グリコシル―エトポシドプロドラツグ及びその製造方法
EP3350192B1 (fr) Composés polysaccharides multi-fonctionnalisés et leur utilisation pour cibler le récepteur du mannose 6-phosphate cation-indépendant
HRP921226A2 (en) Morpholinyl derivatives of doxorubicin and process for their preparation
WO2023216732A1 (zh) 一种幽门螺旋杆菌核心脂多糖寡糖抗原糖链的化学合成方法
EP0136938A2 (fr) Nouveaux dérivés furaniques, leur préparation et leur application
CA2179899C (en) Synthetic glycoamines that promote or inhibit cell adhesion
El Hilali et al. Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy
JP2774429B2 (ja) 糖骨格を有する分枝鎖型誘導体
FR2970969A1 (fr) Oligosaccharides 3-o-alkyles activateurs des recepteurs des fgfs, leur preparation et leur application en therapeutique
EP0824537A1 (fr) Derives iodes de monosaccharides utilisables comme produits radiopharmaceutiques
FR2483928A1 (fr) Derives de la n-trifluoracetyladriamycine, leur preparation et leurs utilisations therapeutiques
Azoulay et al. p-Nitrophenyl β-D-glucopyranosiduronic analogs as potential substrates for β-glucuronidase
BE1008581A3 (fr) Prodrogues, composition pharmaceutique les comprenant et leur utilisation.
CN110691774A (zh) 合成单保护双官能前药的方法和基于其的抗体药物缀合物以及制备抗体药物缀合物的方法
EP0402259A1 (fr) Nouvelles anthracyclines, leur procédé de préparation ainsi que médicaments les contenant

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
WWE Wipo information: entry into national phase

Ref document number: 2109304

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1019930703288

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 08137167

Country of ref document: US